The (−)-morphinanium quaternary salts of opiates such as morphine and codeine have been known for over a century. Because of their ionic charge, these quaternary salts do not traverse the blood brain barrier into the central nervous system, but they do retain good to excellent affinity for peripheral opiate receptors. Consequently, the central nervous system activity of opiates responsible for pain relief is not blocked by quaternary salt derivatives of opiate antagonists, such as R-(−)-methylnaltrexone salt. Accordingly, of R-(−)-methylnaltrexone salt is used to mitigate the side effects (e.g., constipation) of systemic opiate analgesia. Recent research has shown that (−)-morphinanium alkaloid salts are potent inhibitors of vascular endothelial growth factor (VEGF). VEGF inhibitors are important adjuncts in the treatment of various tumors and the treatment of macular degeneration.
More recent work has suggested that VEGF inhibitory activity appears to be independent of the stereochemistry of the morphinan ring system. Thus, (+)-morphinanium quaternary salts may be useful as improved VEGF inhibitors because they would not interact with peripheral opiate receptors. There is a need, therefore, for processes for synthesizing quaternary salts of (+)-morphinan alkaloids.